Efficacy of alpha1-antitrypsin augmentation therapy in conditions other than pulmonary emphysema.

Blanco I, Lara B, de Serres F - Orphanet J Rare Dis (2011)

Bottom Line:
However, the compassionate use of augmentation therapy in recent years has proven outstanding efficacy in small cohorts of patients suffering from uncommon AAT deficiency-related diseases other than pulmonary emphysema, such as fibromyalgia, systemic vasculitis, relapsing panniculitis and bronchial asthma.Moreover, a series of preclinical studies provide evidence of the efficacy of AAT augmentation therapy in several infectious diseases, diabetes mellitus and organ transplant rejection.These facts have generated an expanding number of medical applications and patents with claims for other indications of AAT besides pulmonary emphysema.

ABSTRACTUp to now alpha 1-antitrypsin (AAT) augmentation therapy has been approved only for commercial use in selected adults with severe AAT deficiency-related pulmonary emphysema (i.e. PI*ZZ genotypes as well as combinations of Z, rare and alleles expressing AAT serum concentrations <11 μmol/L). However, the compassionate use of augmentation therapy in recent years has proven outstanding efficacy in small cohorts of patients suffering from uncommon AAT deficiency-related diseases other than pulmonary emphysema, such as fibromyalgia, systemic vasculitis, relapsing panniculitis and bronchial asthma. Moreover, a series of preclinical studies provide evidence of the efficacy of AAT augmentation therapy in several infectious diseases, diabetes mellitus and organ transplant rejection. These facts have generated an expanding number of medical applications and patents with claims for other indications of AAT besides pulmonary emphysema. The aim of the present study is to compile and analyze both clinical and histological features of the aforementioned published case studies and reports where AAT augmentation therapy was used for conditions other than pulmonary emphysema. Particularly, our research refers to ten case reports and two clinical trials on AAT augmentation therapy in patients with both AAT deficiency and, at least, one of the following diseases: fibromyalgia, vasculitis, panniculitis and bronchial asthma. In all the cases, AAT was successfully applied whereas previous maximal conventional therapies had failed. In conclusion, laboratory studies in animals and humans as well as larger clinical trials should be, thus, performed in order to determine both the strong clinical efficacy and security of AAT in the treatment of conditions other than pulmonary emphysema.

Mentions:
In 2008, Blanco I, et al. (Hospital Valle del Nalón, Asturias, Spain) reported the case of a Caucasian 27-year old woman, working as a cleaner, who started to suffer from recurrent dyspnoea, wheezing, cough and chest tightness [70]. A totally reversible and variable spirometric airflow limitation was evidenced, and she was diagnosed with bronchial asthma (Figure 5). In the following years, she was also diagnosed with nasal polyps as well as Aspirin-Sensitive Asthma (ASA). Isoelectric-focusing and nephelometry showed that the patient had a deficient phenotype MZ with intermediate low AAT serum concentrations. On the other hand, PCR genotyping sequenced exons II-V of the AAT gene, diagnosing a genotype M3Z. The results of several studies to rule out other conditions, mimicking or worsening bronchial asthma, were either normal or negative except for immune hyperthyroidism. The patient was firstly treated with Carbimazole and later with radioisotope therapy (causing iatrogenic hypothyroidism but easily managed with Levothyroxine). However, asthma persisted with frequent at night symptoms, daily attacks of dyspnoea and limited physical exertion. As pulmonary function significantly worsened due to asthma attacks, the patient had to use frequently the emergency medical services and even was admitted to hospital in several occasions. She was prescribed long-term prednisone tablets (15-30 mg/day). However, asthma continued to be out of control and bronchial obstruction, permanent. Moreover, significant side effects of glucocorticoid drugs appeared in the following months. As a consequence, the patient experienced severe limitation of her physical capacity which negatively affected her mental state and social and personal life. The results of a computerized axial tomography of the chest to rule out pulmonary emphysema and other intercurrent complications were within normal limits. Due to the unfavourable clinical evolution of the patient, doctors tried a therapeutic trial with AAT augmentation therapy (60 mg/Kg/week dose for the first two weeks and 120 mg/biweekly for 7 months). As the results of the trial were significantly favourable, the treatment continued. The continuous administration of AAT infusions stopped the decline in lung function. In 1991-1994 (period 1) her FEV1 (expressed by mean and standard deviation) was equivalent to 69% (17); in 1995-2003 (period 2) it declined to 43% (5.14); and from 2004, once the AAT augmentation therapy started, to 2007 (period 3), it rose up to 52% (3.75). Statistical significance was found between period 1 and period 2 (p = 0.000), period 1 and period 3 (p = 0.000), and period 2 and period 3 (p = 0.001). As expected, the augmentation therapy increased the AAT serum levels of the patient, measured by nephelometry and expressed in mg/dL, from basal values of 0.78 (0.04) to 1.08 (0.10) pre-infusions and 2.61 (0.34) post-infusions. Moreover, AAT augmentation therapy significantly reduced the number of emergency visits and hospital admissions (22 emergency visits in 2001-2003 vs. 8 in 2004-2007; and 4 hospital admissions in 2002-2003 vs. 1 in 2004-2007). The need for prednisone was also reduced shortly after the beginning of the augmentation therapy, facilitating the elimination of chronic corticoid side effects and progressively reducing the high score of Asthma Quality of Life (AQL) in 2003 from 10 to 3 points in 2007 (Figure 6).

Mentions:
In 2008, Blanco I, et al. (Hospital Valle del Nalón, Asturias, Spain) reported the case of a Caucasian 27-year old woman, working as a cleaner, who started to suffer from recurrent dyspnoea, wheezing, cough and chest tightness [70]. A totally reversible and variable spirometric airflow limitation was evidenced, and she was diagnosed with bronchial asthma (Figure 5). In the following years, she was also diagnosed with nasal polyps as well as Aspirin-Sensitive Asthma (ASA). Isoelectric-focusing and nephelometry showed that the patient had a deficient phenotype MZ with intermediate low AAT serum concentrations. On the other hand, PCR genotyping sequenced exons II-V of the AAT gene, diagnosing a genotype M3Z. The results of several studies to rule out other conditions, mimicking or worsening bronchial asthma, were either normal or negative except for immune hyperthyroidism. The patient was firstly treated with Carbimazole and later with radioisotope therapy (causing iatrogenic hypothyroidism but easily managed with Levothyroxine). However, asthma persisted with frequent at night symptoms, daily attacks of dyspnoea and limited physical exertion. As pulmonary function significantly worsened due to asthma attacks, the patient had to use frequently the emergency medical services and even was admitted to hospital in several occasions. She was prescribed long-term prednisone tablets (15-30 mg/day). However, asthma continued to be out of control and bronchial obstruction, permanent. Moreover, significant side effects of glucocorticoid drugs appeared in the following months. As a consequence, the patient experienced severe limitation of her physical capacity which negatively affected her mental state and social and personal life. The results of a computerized axial tomography of the chest to rule out pulmonary emphysema and other intercurrent complications were within normal limits. Due to the unfavourable clinical evolution of the patient, doctors tried a therapeutic trial with AAT augmentation therapy (60 mg/Kg/week dose for the first two weeks and 120 mg/biweekly for 7 months). As the results of the trial were significantly favourable, the treatment continued. The continuous administration of AAT infusions stopped the decline in lung function. In 1991-1994 (period 1) her FEV1 (expressed by mean and standard deviation) was equivalent to 69% (17); in 1995-2003 (period 2) it declined to 43% (5.14); and from 2004, once the AAT augmentation therapy started, to 2007 (period 3), it rose up to 52% (3.75). Statistical significance was found between period 1 and period 2 (p = 0.000), period 1 and period 3 (p = 0.000), and period 2 and period 3 (p = 0.001). As expected, the augmentation therapy increased the AAT serum levels of the patient, measured by nephelometry and expressed in mg/dL, from basal values of 0.78 (0.04) to 1.08 (0.10) pre-infusions and 2.61 (0.34) post-infusions. Moreover, AAT augmentation therapy significantly reduced the number of emergency visits and hospital admissions (22 emergency visits in 2001-2003 vs. 8 in 2004-2007; and 4 hospital admissions in 2002-2003 vs. 1 in 2004-2007). The need for prednisone was also reduced shortly after the beginning of the augmentation therapy, facilitating the elimination of chronic corticoid side effects and progressively reducing the high score of Asthma Quality of Life (AQL) in 2003 from 10 to 3 points in 2007 (Figure 6).

Bottom Line:
However, the compassionate use of augmentation therapy in recent years has proven outstanding efficacy in small cohorts of patients suffering from uncommon AAT deficiency-related diseases other than pulmonary emphysema, such as fibromyalgia, systemic vasculitis, relapsing panniculitis and bronchial asthma.Moreover, a series of preclinical studies provide evidence of the efficacy of AAT augmentation therapy in several infectious diseases, diabetes mellitus and organ transplant rejection.These facts have generated an expanding number of medical applications and patents with claims for other indications of AAT besides pulmonary emphysema.

ABSTRACTUp to now alpha 1-antitrypsin (AAT) augmentation therapy has been approved only for commercial use in selected adults with severe AAT deficiency-related pulmonary emphysema (i.e. PI*ZZ genotypes as well as combinations of Z, rare and alleles expressing AAT serum concentrations <11 μmol/L). However, the compassionate use of augmentation therapy in recent years has proven outstanding efficacy in small cohorts of patients suffering from uncommon AAT deficiency-related diseases other than pulmonary emphysema, such as fibromyalgia, systemic vasculitis, relapsing panniculitis and bronchial asthma. Moreover, a series of preclinical studies provide evidence of the efficacy of AAT augmentation therapy in several infectious diseases, diabetes mellitus and organ transplant rejection. These facts have generated an expanding number of medical applications and patents with claims for other indications of AAT besides pulmonary emphysema. The aim of the present study is to compile and analyze both clinical and histological features of the aforementioned published case studies and reports where AAT augmentation therapy was used for conditions other than pulmonary emphysema. Particularly, our research refers to ten case reports and two clinical trials on AAT augmentation therapy in patients with both AAT deficiency and, at least, one of the following diseases: fibromyalgia, vasculitis, panniculitis and bronchial asthma. In all the cases, AAT was successfully applied whereas previous maximal conventional therapies had failed. In conclusion, laboratory studies in animals and humans as well as larger clinical trials should be, thus, performed in order to determine both the strong clinical efficacy and security of AAT in the treatment of conditions other than pulmonary emphysema.